Treatment methods having reduced drug-related toxicity and methods of identifying the likelihood of patient harm from prescribed medications

ABSTRACT

Methods of determining whether specific drugs or patients carry an increased risk of causing or developing, respectively, long QT syndrome or Torsades de Pointes and methods of treating such patients.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is an international application claiming the benefit ofpriority of U.S. Provisional Application No. 62/338,704, filed May 19,2016, the entire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The invention described herein relates in general to the development anduse of (1) a drug-specific index computed from distinct drugcharacteristics; and (2) a patient-specific score computed frompredefined values of selected risk factors of drug related toxicity. Insome embodiments, these two aspects of the invention contribute toreduce the likelihood of patient harm arising from prescribedmedications.

BACKGROUND OF THE INVENTION

While medications are a necessary intervention for the prevention andtreatment of disease, disability, and death, they may also causeproblems on a broad scale. One particular side-effect that may beassociated with certain drugs is a perturbation of the heart'scapability to regain its basic membrane potential after a heartbeat.Such condition is associated with a prolongation of the QT interval onthe surface electrocardiogram (ECG) and is generally described asdrug-induced long QT Syndrome (LQTS). Prolongation of the QT intervalmay predispose patients to syncope events and a particular polymorphicventricular tachycardia described as Torsades de Pointes.

Many medications have been implicated in the initiation of drug-inducedLQTS. In the past 20 years, drug-induced QT prolongation and hence,Torsades de Points, has led to withdrawal from the market of at least 6medications and publications of several black box warnings in the UnitedStates. The Food and Drug Administration now requires study of thisphenomenon prior to market approval.

Accordingly, there is a need in the field for methods of treatment thatallow for the avoidance of drug-induced LQTS and methods of identifyingdrugs or drug combinations that may result in drug-induced LQTS.

SUMMARY OF THE INVENTION

The inventions described herein provide a comprehensive approach thatincludes a number of factors that may influence a medication'slikelihood of causing drug-induced LQTS and/or Torsades de Pointes. Insome embodiments, the Long QT-JT Index takes into account the scenariowhere a medication has the greatest chance of causing Torsades dePointes—when a medication is the most “risky.” The following factors maybe considered specific to each medication:

1. IC₅₀ for block of I_(Kr);

2. IC₅₀ for block of I_(Ks);

3. IC₅₀ for block of Nav1.5 (sodium) current;

4. IC₅₀ for block of Cav1.2 (calcium) current;

5. Inhibition of hERG trafficking;

6. Cmax of the drug at a test Dose;

7. Maximum daily dose of the drug according to labelling;

8. Protein binding of the drug; and/or

9. Drug-drug interaction coefficient (DDIC).

In some embodiments, the Drug-drug interaction coefficient takes intoaccount the pharmacokinetics of the medication—whether it has a highextraction ratio (low bioavailability) or low extraction ratio (highbioavailability), relative enzymatic pathways involved in the clearanceof the drug.

While the medication-specific risk index will be helpful whenscrutinizing a single medication, the reality is that patients take manymedications and have individual risk factors that may predispose orprotect them from QT prolongation and Torsades de Pointes.

In some embodiments, a patient-specific Long QT-JT Score is providedthat is dynamic based on the patient's current conditions andconcomitant medications. The risk factors are included based on theevidence described herein, and may be assigned points as follows:

Risk Points Factor Description Range 1 Male or female gender, alsoincludes age for males 0-0.5 2 Heart Rhythm: sinus rhythm, AtrialFibrillation, Sick Sinus 0-1   Syndrome, Pause, Heart Rate, Beta-blockerusage 3 Hypokalemia (K < 3.5 mEq/L); use of triamterene 0-1   4Hypomagnesemia (Mg < 1.5 mEq/L) 0-1   5 Diuretics 0-1   6Antiarrhythmics: Class IA, Class IC, Class III; amiodarone 0-9   7QT-prolonging drugs and drug interactions 0-12  8 QTc interval(Cut-offs: <450, <475, <500, <550, 550+ msec) 0-10 

The scoring mechanisms described herein have been validated againstliterature cases of known Torsades de Pointes. More than 50 cases ofdocumented Torsades de Pointes have been identified due to medicationuse and/or medication interactions and their risk score has beencalculated based on the methods described herein. In such cases, therisk scores are generally above 10.

In some embodiments, the foregoing and other objects and advantages ofthe invention are obtained by using a method for estimating risk ofdrug-related problems either due to drug characteristics or a patient'soverall drug regimen and conditions.

In an embodiment, the invention includes a method for determiningwhether a compound is associated with an increased risk of long QTsyndrome or Torsades de Pointes by determining a drug-specific index. Insome embodiments, the method may include the step of measuring a firstindex variable, which may include determining one or more of (1) an IC₅₀value for block of one or more of I_(Kr), and I_(Ks), (2) a Cmax of thecompound at a test dose, (3) a daily dose amount of the compound, (4) aprotein binding value for the compound at a target protein, and (5) adrug-drug interaction coefficient (DDIC) for the compound. In someembodiments, the method may include the step of measuring a second indexvariable, which may include determining one or more of (1) an IC₅₀ valuefor block of CaV1.2 current, and (2) the IC₅₀ value for block of one ormore of I_(Kr) and I_(Ks). In some embodiments, the method may includethe step of measuring a third index variable, which may includedetermining one or more of (1) an IC₅₀ value for block of NaV1.5current, and (2) the IC₅₀ value for block of one or more of I_(Kr) andI_(Ks). In some embodiments, the method may include the step ofmeasuring a fourth index variable, which may include determining afourth index variable, which may include determining a qualitative valuefor the compound's inhibition of hERG trafficking. In some embodiments,the method may include the step of combining the first, second, third,and/or fourth index variables to provide the drug-specific index, whichis indicative of an increased risk of long QT syndrome or Torsades dePointes. In some embodiments, a drug-specific index of less than 15 isindicative of an increased risk of long QT syndrome or Torsades dePointes. In some embodiments, a drug-specific index of greater than 15is not indicative of an increased risk of long QT syndrome or Torsadesde Pointes.

In an embodiment, the invention includes a method for determiningwhether a patient undergoing treatment with a compound has an increasedrisk of long QT syndrome or Torsades de Pointes by determining apatient-specific score. In some embodiments, the method may include thesteps of: (1) determining a risk variable based on the patient's genderand age; (2) measuring the patient's heart rhythm including detectingone or more of a sinus rhythm, atrial fibrillation, sick sinus syndrome,pause, and heart rate; (3) detecting a potassium level in the patient;(4) detecting a magnesium level in the patient; (5) detecting thepresence of one or more diuretics or antiarrhythmics in the patient; (6)measuring a drug-specific index for one or drug therapeutics in thepatient's treatment regimen; and (7) measuring the patient's QTinterval. In some embodiments, the method may further include the stepof calculating the patient-specific score based on quantitative resultscollected from the steps of: (1) determining a risk variable based onthe patient's gender and age; (2) measuring the patient's heart rhythmincluding detecting one or more of a sinus rhythm, atrial fibrillation,sick sinus syndrome, pause, and heart rate; (3) detecting a potassiumlevel in the patient; (4) detecting a magnesium level in the patient;(5) detecting the presence of one or more diuretics or antiarrhythmicsin the patient; (6) measuring a drug-specific index for one or drugtherapeutics in the patient's treatment regimen; and (7) measuring thepatient's QT interval. In some embodiments, a patient-specific score ofgreater than 10 is indicative of an increased risk of long QT syndromeor Torsades de Pointes. In some embodiments, a patient specific score ofless than 10 is not indicative of an increased risk of long QT syndromeor Torsades de Pointes.

In an embodiment, the invention includes a method for determiningwhether a patient undergoing treatment with a compound has an increasedrisk of long QT syndrome or Torsades de Pointes by determining a patientspecific score, which may include the steps of: (1) determining a riskvariable having a value based on the patient's gender and/or age; (2)determining a risk variable having a value based on the patient's heartrhythm, which may include determining one or more of the patient's sinusrhythm, atrial fibrillation, sick sinus syndrome, pause, heart rate, andbeta-blocker usage; (3) determining a risk variable having a value basedon the patient having hypokalemia (i e , a potassium level of less than3.5 mEq/L) and/or the patient's use of triamterene; (4) determining arisk variable having a value based on the patient having hypomagnesemia(i.e., a magnesium level of less than 1.5 mEq/L); (5) determining a riskvariable having a value based on the patient's use of diuretics; (6)determining a risk variable having a value based on the patient's use ofan antiarrhythmic, such as, for example, a Class IA, Class IC, or ClassIII antiarrhythmic, or amiodarone; (7) determining a risk variablehaving a value based on the patient's use of QT-prolonging drugs and/orthe presence of drug-drug interactions, which may include themeasurement of a drug-specific index and/or a drug-drug interactioncoefficient (DDIC) for the QT-prolonging drugs used by the patient; and(8) determining a risk variable having a value based on the patient'sQTc interval. In some embodiments, the method may further include thestep of calculating the patient-specific score based on an analysis ofthe risk variables determined in the steps of: (1) determining a riskvariable having a value based on the patient's gender and/or age; (2)determining a risk variable having a value based on the patient's heartrhythm, which may include determining one or more of the patient's sinusrhythm, atrial fibrillation, sick sinus syndrome, pause, heart rate, andbeta-blocker usage; (3) determining a risk variable having a value basedon the patient having hypokalemia (i e , a potassium level of less than3.5 mEq/L) and/or the patient's use of triamterene; (4) determining arisk variable having a value based on the patient having hypomagnesemia(i.e., a magnesium level of less than 1.5 mEq/L), (5) determining a riskvariable having a value based on the patient's use of diuretics; (6)determining a risk variable having a value based on the patient's use ofan antiarrhythmic, such as, for example, a Class IA, Class IC, or ClassIII antiarrhythmic, or amiodarone; (7) determining a risk variablehaving a value based on the patient's use of QT-prolonging drugs and/orthe presence of drug-drug interactions, which may include themeasurement of a drug-specific index and/or a drug-drug interactioncoefficient (DDIC) for the QT-prolonging drugs used by the patient; and(8) determining a risk variable having a value based on the patient'sQTc interval. In some embodiments, a patient-specific score of greaterthan 10 is indicative of an increased risk of long QT syndrome orTorsades de Pointes. In some embodiments, a patient specific score ofless than 10 is not indicative of an increased risk of long QT syndromeor Torsades de Pointes.

In an embodiment, the invention includes a method of treating patientshaving an increased risk of developing long QT syndrome or Torsades dePointes due to a patient-specific score of greater than 10. In someembodiments, the method may include the administration of atherapeutically effective amount of a compound selected from the groupconsisting of a potassium salt and a magnesium salt. In someembodiments, the potassium salt may be potassium chloride. In someembodiments, the magnesium salt may be magnesium sulfate.

In an embodiment, the invention includes a method of treating a patientwith a compound determined to increase the risk of long QT syndrome orTorsades de Pointes. In some embodiments, the method may include thestep of confirming that the patient does not have an increased risk ofdeveloping long QT syndrome or Torsades de Pointes due to apatient-specific score of greater than 10. In some embodiments, themethod may include the step of administering a pharmaceuticalcomposition to the patient including a therapeutically effective amountof the compound or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier. In some embodiments, the compounddetermined to increase the risk of long QT syndrome or Torsades dePointes may include one or more of Albuterol, Alfuzosin, Amantadine,Amiodarone, Amitriptyline, Amphetamine, Arsenic trioxide, Astemizole,Atazanavir, Atomoxetine, Azithromycin, Bepridil, Chloral hydrate,Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram,Clarithromycin, Clomipramine, Clozapine, Cocaine, Desipramine,Dexmethylphenidate, Diphenhydramine, Diphenhydramine, Disopyramide,Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin,Dronedarone, Droperidol, Ephedrine, Epinephrine, Erythromycin,Escitalopram, Escitalopram, Famotidine, Felbamate, Fenfluramine,Flecamide, Fluconazole, Fluoxetine, Foscarnet, Fosphenyloin,Galantamine, Gatifloxacin, Gemifloxacin, Granisetron, Halofantrine,Haloperidol, Ibutilide, Imipramine, Indapamide, Isoproterenol,Isoproterenol, Isradipine, Itraconazole, Ketoconazole, Lapatinib,Lapatinib, Levalbuterol, Levofloxacin, Levomethadyl, Lisdexamfetamine,Lithium, Mesoridazine, Metaproterenol, Methadone, Methylphenidate,Midodrine, Moexipril/HCTZ, Moxifloxacin, Nicardipine, Nilotinib,Norepinephrine, Nortriptyline, Octreotide, Ofloxacin, Ondansetron,Oxytocin, Paliperidone, Paroxetine, Pentamidine, Perflutren lipidmicrospheres, Phentermine, Phenylephrine, Phenylpropanolamine, Pimozide,Probucol, Procainamide, Protriptyline, Pseudoephedrine, Quetiapine,Quinidine, Ranolazine, Risperidone, Ritodrine, Ritonavir, Roxithromycin,Salmeterol, Sertindole, Sertraline, Sibutramine, Solifenacin, Sotalol,Sparfloxacin, Sunitinib, Tacrolimus, Tamoxifen, Telithromycin,Terbutaline, Terfenadine, Thioridazine, Tizanidine, Tolterodine,Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib, Vardenafil,Venlafaxine, Voriconazole, Ziprasidone, and the pharmaceuticallyacceptable salts thereof.

In an embodiment, the invention may include a method of treating apatient with a compound determined to increase the risk of long QTsyndrome or Torsades de Pointes, which may include the step ofadministering a pharmaceutical composition to the patient including atherapeutically effective amount of the compound or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. Insome embodiments, the method may include the step of determining whetherthe patient has an increased risk of developing long QT syndrome orTorsades de Pointes due a patient-specific score that is indicative ofan increased risk of developing long QT syndrome or Torsades de Pointes.In some embodiments, the patient-specific score that is indicative of anincreased risk of developing long QT syndrome or Torsades de Pointes isgreater than 10. In some embodiments, the method may further includehalting treatment of the patient with the pharmaceutical composition. Insome embodiments, the method may further include the administration ofan additional pharmaceutical composition to the patient that does notinclude the compound. In some embodiments, the additional pharmaceuticalcomposition includes an additional compound that has a drug-specificindex of greater than 15.

In some embodiments, the methods described herein may utilize anon-transitory computer readable medium having program instructionsstored in a memory device, the instructions executable by a processor todirect the performance of operations to estimate drug-related orpatient-related risk. In some embodiments, the program instructions fordetermining drug-specific index for a drug or combination of drugs maycomprise the steps of:

importing a first data set comprising IC₅₀ for block of I_(Kr) and/orI_(Ks), IC₅₀ for block of Nav1.5 (sodium) current, IC₅₀ for block ofCav1.2 (calcium) current, a qualitative value for inhibition of hERGtrafficking, Cmax of the drug at a test dose, daily dose of the drugbeing used, and/or protein binding of the drug or combination of drugs;and importing a second data set comprising metabolic pathways and extentof metabolism of the drug or combination of drugs as well as the degreeof competitive inhibition from other drugs or combinations of drugs in apatient's drug regimen to establish a drug-drug interaction coefficient(DDIC).

In some embodiments, the program instructions for determining apatient-specific score may comprise the steps of:

importing a data set comprising gender, age, heart rhythm—whether sinusrhythm, atrial fibrillation, sick sinus syndrome, pause, heart rate—andbeta-blocker usage, hypokalemia, hypomagnesemia, diuretic use,antiarrhythmic use, Long QT-JT Index value of each drug used by thispatient, QTc interval, ongoing drugs and drug-drug interactions. In someembodiments, data set forth herein may be processed by eight pre-definedalgorithms to calculate patient-specific Long QT-JT Scores.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofthe invention, will be better understood when read in conjunction withthe appended drawings.

FIG. 1 is a chart illustrating the Z-distribution of Long QT-JT Indexfor 155 drugs.

FIG. 2 is a chart illustrating the algorithm used for calculation ofrisk factor 1.

FIG. 3 is a chart illustrating the algorithm used for calculation ofrisk factor 2.

FIG. 4 is a chart illustrating the algorithm used for calculation ofrisk factor 3.

FIG. 5 is a chart illustrating the algorithm used for calculation ofrisk factor 4.

FIG. 6 is a chart illustrating the algorithm used for calculation ofrisk factor 5.

FIG. 7 is a chart illustrating the algorithm used for calculation ofrisk factor 6.

FIG. 8 is a chart illustrating the algorithm used for calculation ofrisk factor 7.

FIG. 9 is a chart illustrating the algorithm used for calculation ofrisk factor 8.

FIG. 10 is a chart illustrating the input of an example patient'sparameters into the Long QT-JT Score.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference in their entireties.

Definitions

The terms “co-administration,” “co-administering,” “administered incombination with,” “administering in combination with,” “simultaneous,”and “concurrent,” as used herein, encompass administration of two ormore active pharmaceutical ingredients to a subject so that both activepharmaceutical ingredients and/or their metabolites are present in thesubject at the same time. Co-administration includes simultaneousadministration in separate compositions, administration at differenttimes in separate compositions, or administration in a composition inwhich two or more active pharmaceutical ingredients are present.Simultaneous administration in separate compositions and administrationin a composition in which both agents are present are preferred.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound or combination of compounds as describedherein that is sufficient to effect the intended application including,but not limited to, disease treatment. A therapeutically effectiveamount may vary depending upon the intended application (in vitro or invivo), or the subject and disease condition being treated (e.g., theweight, age and gender of the subject), the severity of the diseasecondition, the manner of administration, etc. which can readily bedetermined by one of ordinary skill in the art. The term also applies toa dose that will induce a particular response in target cells (e.g., thereduction of platelet adhesion and/or cell migration). The specific dosewill vary depending on the particular compounds chosen, the dosingregimen to be followed, whether the compound is administered incombination with other compounds, timing of administration, the tissueto which it is administered, and the physical delivery system in whichthe compound is carried.

The terms “drug-specific index” or “drug-specific LQTS index” or “LongQT-JT Index” are interchangeable and refer to a value determinedaccording to the methods described herein for a drug, which isindicative of the drug's propensity for causing long QT syndrome orTorsades de Pointes. As described herein, a drug-specific index of lessthan 15 is associated with an increased risk of causing long QT syndromeor Torsades de Pointes. In some embodiments, a drug-specific index ofless than about 15 is associated with an increased risk of causing longQT syndrome or Torsades de Pointes.

The terms “patient-specific score” or “patient-specific LQTS score” or“patient-specific Long QT-JT score” are interchangeable and refer to avalue determined according to the methods described for a patient, whichis indicative of the patient's risk for developing long QT syndrome orTorsades de Pointes. As described herein, a patient-specific score ofgreater than 10 is associated with an increased risk of developing longQT syndrome or Torsades de Pointes. In some embodiments, apatient-specific score of greater than about 10 is associated with anincreased risk of developing long QT syndrome or Torsades de Pointes.

A “therapeutic effect” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit. A prophylactic effectincludes delaying or eliminating the appearance of a disease orcondition, delaying or eliminating the onset of symptoms of a disease orcondition, slowing, halting, or reversing the progression of a diseaseor condition, or any combination thereof.

The term “pharmaceutically acceptable salt” refers to salts derived froma variety of organic and inorganic counter ions known in the art.Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Preferred inorganic acids from whichsalts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.Preferred organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid andsalicylic acid. Pharmaceutically acceptable base addition salts can beformed with inorganic and organic bases. Inorganic bases from whichsalts can be derived include, for example, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese andaluminum. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins. Specific examples include isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. In some embodiments, the pharmaceutically acceptable baseaddition salt is chosen from ammonium, potassium, sodium, calcium, andmagnesium salts. The term “cocrystal” refers to a molecular complexderived from a number of cocrystal formers known in the art. Unlike asalt, a cocrystal typically does not involve hydrogen transfer betweenthe cocrystal and the drug, and instead involves intermolecularinteractions, such as hydrogen bonding, aromatic ring stacking, ordispersive forces, between the cocrystal former and the drug in thecrystal structure.

“Pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” is intended to include any and all solvents, dispersionmedia, coatings, antibacterial and antifungal agents, isotonic andabsorption delaying agents, and inert ingredients. The use of suchpharmaceutically acceptable carriers or pharmaceutically acceptableexcipients for active pharmaceutical ingredients is well known in theart. Except insofar as any conventional pharmaceutically acceptablecarrier or pharmaceutically acceptable excipient is incompatible withthe active pharmaceutical ingredient, its use in the therapeuticcompositions of the invention is contemplated. Additional activepharmaceutical ingredients, such as other drugs, can also beincorporated into the described compositions and methods.

When ranges are used herein to describe, for example, physical orchemical properties such as molecular weight or chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. Use of the term “about” whenreferring to a number or a numerical range means that the number ornumerical range referred to is an approximation within experimentalvariability (or within statistical experimental error), and thus thenumber or numerical range may vary. The variation is typically from 0%to 15%, preferably from 0% to 10%, more preferably from 0% to 5% of thestated number or numerical range. The term “comprising” (and relatedterms such as “comprise” or “comprises” or “having” or “including”)includes those embodiments such as, for example, an embodiment of anycomposition of matter, method or process that “consist of” or “consistessentially of” the described features.

For the avoidance of doubt, it is intended herein that particularfeatures (for example integers, characteristics, values, uses, diseases,formulae, compounds or groups) described in conjunction with aparticular aspect, embodiment or example of the invention are to beunderstood as applicable to any other aspect, embodiment or exampledescribed herein unless incompatible therewith. Thus such features maybe used where appropriate in conjunction with any of the definition,claims or embodiments defined herein. All of the features disclosed inthis specification (including any accompanying claims, abstract anddrawings), and/or all of the steps of any method or process sodisclosed, may be combined in any combination, except combinations whereat least some of the features and/or steps are mutually exclusive. Theinvention is not restricted to any details of any disclosed embodiments.The invention extends to any novel one, or novel combination, of thefeatures disclosed in this specification (including any accompanyingclaims, abstract and drawings), or to any novel one, or any novelcombination, of the steps of any method or process so disclosed.

QT Prolongation and Development of Torsades de Pointes following Long QTInterval

The cardiomyocyte plasma membrane is, in principle, impermeable to ionflow. Thus, influx and efflux of ions can occur only following theopening of voltage-gated or agonist-gated ion channels or through theaction of ion transporters (pumps). With respect to these channels andtransporters underlying the ventricular action potential and, hence, thecorresponding surface ECG waves, Phase 4 of the action potentialcorresponds to ventricular diastole when ventricular myocytes are attheir resting potential. At this stage, the concentration of K⁺ ishigher inside the cell than outside; and the concentration of Na⁺ andCa²⁺ are higher outside the cells than inside. Only specific K⁺ channels(I_(KI), K_(Kach), I_(KATP)) will show some openings during this phasecreating an inward electrical gradient (as positive charges like K⁺prefer to stay inside the cells, which have a negative potential) and anoutward chemical gradient (as K⁺ prefers to exit the intracellularmilieu where there is a large concentration of this ion compared to theextracellular cleft).

When extracellular K⁺ concentration is 3.5 mM and intracellular K⁺ is150 mM, the system comes into equilibrium at a voltage of −80 mV.

Phase 0 of the action potential is characterized by the opening ofvoltage-gated Na⁺ channels when the plasma membrane reaches −70 mV.Hence, a rapid influx of Na⁺ occurs due to both an inward chemicalgradient and an inward electrical gradient. As transmembrane potentialreaches −50 mV, voltage-gated Ca²⁺ channels open allowing inward flow ofCa²⁺. On one hand, the increase in intracellular Na⁺ depolarizes thenearby cells (as Na⁺ flows through gap junctions between cardiacmyocytes) and assures propagation of the influx. On the other hand, theincrease in intracellular Ca²⁺ will trigger calcium release(calcium-induced calcium release) from the sarcoplasmic reticulum andcontraction will occur. The depolarization of ventricular cardiacmyocytes and the conduction of the influx throughout the ventricles isdepicted on the surface ECG by the QRS wave.

This is followed by Phase 1, where there is some outward transient K⁺current and a decreased inward Na⁺ current; Phase 1 corresponds to anearly repolarization phase where some transient K⁺ channels open(I_(to)). The presence of I_(to) differentiates between endocardial,epicardial, and M cells.

Phase 2 is considered the plateau phase. During this phase there isroughly equivalent influx of Ca²⁺ via L-type channels in proportion tothe efflux of K⁺—this is the systole of the ventricles during whichactin and myosin interact.

Phase 3—the recovery phase—involves a decrease in inward Ca²⁺ influx, arecovery of intracellular Ca²⁺ by the sarcoplasmic reticulum, and asignificant increase in the efflux of K⁺. Within the K⁺ efflux, thereare two main channels to consider. The channel I_(Kr), synonymous withhERG-KCNH2+Mirp1-KCNE2, is responsible for the rapid repolarization,whereas delayed repolarization is attributed to I_(Ks)(KvLQT1−KCNQ1+mink+KCNE1.

Finally, Phase 4 is the cell's return to its resting membrane potential.

There are many factors that can impact a ventricular cell's capacity torepolarize. As discussed above, repolarization of ventricular myocytesprimarily occurs in Phase 3 via the efflux of K⁺ through I_(Kr) andI_(Kr) channels. Block of I_(Kr) alone may be associated withsignificant prolongation of the QTc interval as the major outwardcurrent at physiological heart rates. The slow component (I_(Ks)) is areserve current which contributes to repolarization when APD isprolonged due to dysfunctional I_(Kr), or, to the contrary, when heartrate accelerates. Indeed, it is the accumulation of I_(Ks) (which isslow to open but also slow to close) that explains shortening of the APDat faster heart rates. Block of I_(Ks) by itself has little effect onthe APD at physiological heart rates, but changes QT the rate adaptationcurve.

Inappropriate inactivation of the late Na⁺ current (SNC5A: windowcurrent) can also prolong the ventricular action potential duration.Mutations in the various components of I_(Kr), I_(Ks), and I_(Na) haveall been associated with the inherited and drug-induced forms of LQTS.If a single repolarization mechanism is disturbed, there may be littleto no effect on the QT interval; however, if multiple mechanisms areimpaired, there may be clinically significant effects on QTc intervaland risk of Torsades de Pointes.

There are varying degrees to which medications can affect the QTinterval based on various properties. Studies have been performed toanalyze the effect of certain medications on the QT interval length, aswell as the relationship between QT interval length, as well as therelationship between QT interval and adverse outcomes, the mostsignificant being sudden cardiac death. Studies have been carried out toexamine patients who had previously taken medications in certaincategories, which were known to result in a known Torsades de Pointesrisk, conditional Torsades de Pointes risk, and possible Torsades dePointes risk. It has been found that the QTc interval is prolonged by 15milliseconds when patients are given a drug categorized as “known”Torsades de Pointes risk; whereas, for drugs with “possible” Torsades dePointes risk; the QTc lengthened by 3 milliseconds.

When certain studies looked at the addition of a 2nd or 3rd QTcprolonging drug to the patient's regimen, it produced no substantialincrease in QTc. Without being limited to any one theory, if the 2ndand/or 3rd medication prolongs the QTc interval by the same mechanism,then there is little room for QTc prolongation beyond what the 1stmedication caused. The clinical significance of QTc prolongation lieswith the risk that Torsades de Pointes can degenerate into ventricularfibrillation, causing sudden cardiac death. This progression is morecommon with long episodes of Torsades de Pointes, which are also morecommonly, but has also been related to QTc interval length.

In relating the QTc interval to Torsades de Pointes, specifically, ithas been estimated that each 10 millisecond increase in QTc correspondsto a 5-7% exponential increase in risk for Torsades de Pointes. Anotherstudy has demonstrated that 89.5% of drug-induced Torsades de Pointesoccurred when QTc was greater than 500 msec. In general, Torsades dePointes is rare when QTc is <500 ms, accounting for less than 10% of allcases.

Certain studies have shown a relationship between QTc length andmortality, reinforcing the need to take action when a prolonged QTc isidentified. Another study indicated that mortality from any cause forpatients with QTc of 500 ms or greater is 19% (87 out of 470) comparedto 5% for those with QTc less than 500 ms (total 51,434 patients)(p<0.001). Specifically, certain studies showed that the QTc interval asa significant predictor of mortality with a hazard ratio of 1.13(1.12-1.14, p<0.001), meaning patients with a prolonged QTc interval are13% more likely to experience death than those with a normal QTcinterval length.

Method of Determining Drug-Specific LQTS Index

In some embodiments, the invention described herein includes methods fordetermining a drug-specific LQTS index to determine a drug orcombination of drugs likelihood of causing drug-induced LQTS or Torsadesde Pointes. The Long QT-JT Index described herein takes into account thescenario where a medication has the greatest chance of causing Torsadesde Pointes, when a medication may be viewed as risky. In someembodiments, the following factors may be considered specific to eachmedication under consideration:

1. IC₅₀ for block of I_(Kr);

2. IC₅₀ for block of I_(Ks);

3. IC₅₀ for block of Nav1.5 (sodium) current;

4. IC₅₀ for block of Cav1.2 (calcium) current;

5. Inhibition of hERG trafficking;

6. Cmax of the drug at a test dose;

7. Maximum daily dose of the drug according to labelling;

8. Protein binding of the drug; and/or

9. Drug-drug interaction coefficient (DDIC).

As described herein, each of the ion currents may increase or decrease adrug's propensity to cause Torsades de Pointes. The DDIC takes intoaccount the pharmacokinetics of the medication: whether it has a highextraction ratio (low bioavailability) or low extraction ratio (highbioavailability). This is important since changes in concentration willoccur with varying magnitudes.

In embodiment, a method for determining a drug's Long QT-JT index is asdescribed herein. In some embodiments, the method may include measuringa drug's:

1. IC₅₀ for block of I_(Kr) (in μM);

2. IC₅₀ for block of I_(Ks) (in μM);

3. IC₅₀ for block of Nav1.5 (sodium) current (in μM);

4. IC₅₀ for block of Cav1.2 (calcium) current (in μM);

5. Inhibition of hERG trafficking (true or false);

6. Cmax of the drug at a test dose (in nM);

7. Maximum daily dose of the drug according to labeling (in moles);

8. Protein binding of the drug (in percent binding at the listed proteintarget); and/or

9. Drug-drug interaction coefficient (DDIC) (see below).

Upon measuring the foregoing variables, the Long QT-JT Index may becalculated based on the following equation:

Long QT-JT Index=K1+K2′+K3′+K4′, where

$\begin{matrix}{{K\; 1} = \frac{\left( {{IC}_{50}\mspace{14mu}{of}\mspace{14mu} I_{Kr}\mspace{14mu}{or}\mspace{14mu} I_{Ks}\mspace{14mu}{block}} \right) \times 1000}{\begin{matrix}{\left( {\left( {{Cmax}\mspace{14mu}{Dose}\mspace{14mu}{Test}} \right) \times \frac{100 \times {- {Protein}}\mspace{14mu}{Binding}\mspace{14mu}\%}{100}} \right) \times} \\\left( \frac{{Daily}\mspace{14mu}{Dose}\mspace{14mu}{Administered}\mspace{14mu}\left( {µ\;{moles}} \right)}{{Dose}\mspace{14mu}{Test}\mspace{14mu}\left( {µ\;{mole}} \right) \times {DDIC}} \right)\end{matrix}}} \\{{K\; 2} = \frac{{IC}_{50}\mspace{14mu}{for}\mspace{14mu}{block}\mspace{14mu}{of}\mspace{14mu}{{Ca}V}\; 1.2{\mspace{11mu}\;}{current}}{{IC}_{50}\mspace{14mu}{for}\mspace{14mu}{lock}\mspace{14mu}{of}\mspace{14mu} I_{Kr}\mspace{14mu}{or}{\mspace{11mu}\;}I_{Ks}}} \\{{K\; 3} = \frac{{IC}_{50}\mspace{14mu}{for}\mspace{14mu}{block}\mspace{14mu}{of}\mspace{14mu}{{Na}V}\; 1.5{\mspace{11mu}\;}{current}}{{IC}_{50}\mspace{14mu}{for}\mspace{14mu}{block}\mspace{14mu}{of}\mspace{14mu} I_{Kr}\mspace{14mu}{or}{\mspace{11mu}\;}I_{Ks}}} \\{{K\; 4} = {{Inhibition}\mspace{14mu}{of}{\mspace{14mu}\;}{hERG}\mspace{14mu}{trafficking}}}\end{matrix}$

With regard to K2, if K2 is less than 1, then K2′ is 10. If K2 isbetween 1 to less than 5, then K2′ is 5. If K2 is between 5 and lessthan 10, then K2′ is 2.

With regard to K3, if K3 is less than 1, then K3′ is 10. If K3 isbetween 1 to less than 5, then K3′ is 5. If K3 is between 5 and lessthan 10, then K3′ is 2.

With regard to K4, if K4 is true and the drug is an inhibitor of hERGtrafficking, then K4′ is −5. If K4 is false and the drug is not aninhibitor of hERG trafficking, then K4′ is 0. Therefore, if K4 is true,then subtract 5 from the sum of K1, K2′, and K3′.

In some embodiments, drugs having a Long QT-JT Index of less than 15 arelikely to carry a high risk of Torsades de Pointes (i.e.,(K1+K2′+K3′+K4′)<15).

In some embodiments, the Drug-Drug Interaction Coefficient (DDIC) takesinto account the pharmacokinetics of a particular drug or medication:whether it has a high extraction ratio (low bioavailability) or lowextraction ratio (high bioavailability). These aspects should beconsidered because changes in concentration will occur with varyingmagnitudes, with the percent change in concentration calculated per theequations below:

High Extraction Drugs=1/F

Low Extraction Drugs=[100/(100−MP)], where MP is the relativecontribution of major metabolic pathways to drug clearance (CL) as:

CL=CL _(ren) +CL _(1A2) +CL _(2B6) +CL _(2C9) +CL _(2C19) +CL _(2D6) +CL_(3A4) +CL _(3A5) +CL _(transporters) +CL . . .

As an example, mexiletine has F=95% (low extraction ratio, highbioavailability) and 75% is cleared by CYP2D6. If the CYP2D6 enzyme isinhibited, its concentration could increase by 100/(100−MP), or100/(100−75), roughly equivalent to a 4-fold increase in mexiletineconcentration over the course of multiple doses.

In another example, simvastatin has F=5% (high extraction ratio, lowbioavailability). If mechanisms underlying this low bioavailability areinhibited (CYP3A4 enzyme, transporters such as SLCO1B1, favoredabsorption), its concentration could increase by 1/F, or 1/0.05, roughlyequivalent to a 20-fold increase in simvastatin concentration, almostimmediately.

The sensitivity of the Long QT-JT Index described herein is about 86.8%,meaning that it captures roughly 87% of all medications that have beenclinically shown to have effects on the QT interval and/or Torsades dePointes. The specificity of the Long QT-JT Index is 68.1%, meaning itcaptures more medications as high risk (low score) than CredibleMedsclassifies as being known Torsades de Pointes.

Without being limited to any one theory, there may be a few reasons forthis finding. First of all, the Long QT-JT Index captures the maximumrisk scenarios, where a drug is administered at a maximal dose underconditions of a drug interaction. CredibleMeds may not be taking thisinto account (or these medications may mostly fall under their“conditional Torsades de Pointes risk” category). Another possibleexplanation is that there is limited evidence published at this time toguide CredibleMeds classification strategy. Unfortunately, they aredependent on cases occurring and being published in order to classifymedications with high risk.

Overall, it will be beneficial to pharmacists, prescribers, andregulatory agencies to have a pre-emptive, quantitative view of whatcould occur under maximal risk conditions.

Estimating Risk Factors Associated with Torsades de Pointes

In some embodiments, a number of Torsades de Pointes risk factors may beaddressed when determining or otherwise estimating risk of Torsades dePointes in a specific patient. These risk factors include female gender,age, existence of bradycardia, existence of hypokalemia, existence ofhypomagnesemia, use of diuretics, use of medications that affect cardiacrepolarization, existence of pharmacokinetic and pharmacodynamicinteractions, existence of non-modifiable risk factors, existence ofco-morbidities that may have an effect on QTc interval.

Female Gender. In a study, women accounted for 67.2% of all Torsades dePointes cases. The sex difference in QTc interval is due to QTshortening in males after puberty, as they produce increasing levels oftestosterone, rather than a lengthening of QTc in females during theirreproductive years. While there is a difference in baseline QTcinterval, both sexes respond similarly to given QTc-prolongingmedications. Certain studies found no difference in the degree of QTcprolongation between sexes after administration of dofetilide,quinidine, ranolazine, or verapamil.

Age. A study demonstrated that women over their entire lifetime have aQT that is 5-10 milliseconds longer than men, although the differencemay get smaller with age. As men age, their QT interval lengthens, withan overall difference of 10-15 milliseconds from younger males. This wasalso confirmed by another study, which found in a sub-group analysisthat there was no difference in QTc values in either gender over the ageof 50 (i.e., women only have comparably longer QTc at younger ages).Another study estimated that around age 50, men and women have similarQTc intervals again. Thus, age may be considered when assessingdifference in QT due to gender.

Existence of Bradycardia. The existence of bradycardia may beperson-specific, or may be induced by certain medications, e.g.,beta-blockers. Use of beta-blockers may lead to underestimating the QTcinterval, and thus underestimating a patient's risk of Torsades dePointes. Another risk of bradycardia is that I_(Kr) blockers prolong therepolarization time more at slower heart rates, thus compounding therisk of prolonged QTc at slower heart rates with magnified I_(Kr) block.At slower heart rates, there is increased heterogeneity ofrepolarization, which in turn increases risk of proarrhythmias. Theshort-long sequence seen frequently before initiation of Torsades dePointes also increases the heterogeneity of repolarization times, whichincreases the likelihood of reentrant excitation.

Existence of Hypokalemia. Low extracellular potassium (clinicalhypokalemia) paradoxically prevents sufficient potassium current to flowout of the cell through I_(Kr) or I_(Ks), which prolongs the actionpotential, increasing risk for Torsades de pointes. Two proposedmechanisms include enhanced channel inactivation or exaggeratedcompetitive blockage by Na⁺. For example, sodium ion's typicalinhibitory effect on K⁺ channels may become more apparent when there isless competition from K⁺. Another mechanism relates to the fact thatinactivation of K⁺ channels increases inversely with extracellular K⁺levels. Thus, hypokalemia will cause more K⁺ channels to be in theinactivated state and fewer will be available to transfer K⁺ out of thecell during the action potential. Hypokalemia may also increasedrug-binding to the channel, resulting in prolonged repolarization.There are other potential mechanisms that relate hypokalemia to Torsadesde Pointes, including CaM kinase activation increasing the late Na⁺current.

Existence of Hypomagnesemia. Magnesium is a cofactor in functioning ofvoltage-gated K⁺ channels. With low Mg²⁺ levels, mechanistically theremay be overall less functional I_(Kr) and/or I_(Ks), which could prolongthe action potential. Without being limited to any one theory, magnesiumion's role in increasing risk of Torsades de Pointes is due to itsmodulatory effects on L-type Ca²⁺ channels. Generally, higher Mg²⁺levels decrease the inward Ca²⁺ current, shortening phase 2 (plateau) ofthe action potential. With less Mg²⁺, there may be less inhibition ofL-type Ca²⁺ channels (more functional Ca²⁺ channels), which wouldprolong the action potential. This may be observed in practice, asintravenous Mg²⁺ infusions are often successfully used to treat Torsadesde Pointes.

Use of Diuretics. As described herein, electrolyte disturbances,especially hypokalemia, may predispose a patient to Torsades de Pointes.The most commonly implicated diuretics are thiazide-type and loopdiuretics, with their propensity to induce hypokalemia. Indapamide hasbeen reported to inhibit I_(Ks) in addition to causing hypokalemia, andhas been associated with cases of Torsades de Pointes. This blockage ofK⁺ current can be most detrimental when a coadministered agent blocksI_(Kr), thus rendering both K⁺ efflux mechanisms inadequate. Whiletriamterene can prevent hypokalemia, it has been associated withsignificant block of I_(Kr) and I_(Ks). Thus, the use of diureticsshould be considered in the overall risk picture for Torsades dePointes.

Use of Medications that Affect Cardiac Repolarization. Class IA andClass III antiarrhythmics are used therapeutically to prevent reentrantarrhythmias. Prevention is accomplished through extending the actionpotential's duration—thus causing a lengthening of the refractoryperiod—as depicted by the QT interval on a surface ECG. However,extending the QT interval too long may add risk of earlyafterdepoloarizations (EAD). For example, quinidine, dofetilide, andsotalol cause Torsades de Pointes in 1-5% of patients. Amiodaroneroutinely prolongs QT, but rarely causes Torsades de Pointes, as it alsoblocks L-type Ca²⁺ currents and decreases the likelihood of EADformation. Investigating other mechanisms of reducing Torsades dePointes risk, a prospective clinical trial demonstrated that blockingthe late Na⁺ current can offset some of the QTc prolongation effects ofcertain medications.

Many medications that are associated with QT prolongation are implicateddue to block of I_(Kr). It has been shown that most drugs that blockI_(Kr) do so by binding to the intracellular domain. Some of themedications removed from the market due to these concerns includefenfluramine/dexfenfluramine, terfenadine, sertindole, astemizole,grepafloxacin, and cisapride. Since this time, the FDA has requiredthorough QT studies as part of the approval process, generally comparingthe novel agent to moxifloxacin.

A specific example where a medication blocks I_(Kr), but does notincrease risk of Torsades de Pointes is with ranolazine. Ranolazineblocks I_(Kr), but prevents experimental Torsades de Pointes potentiallydue to its inhibitory effect on Na⁺ influx during the plateau (Phase 2)of the action potential. QTc prolongation due to I_(Kr) effects may alsobe due to impaired k_(r) component trafficking, where there is lessfunctioning I_(Kr) channels to transfer the K⁺ channels out of the cell.

Some have tried to quantify the contribution of I_(Kr) block towards therisk of QT prolongation and Torsades de Pointes. For example, a studycreated a quantitative medication-specific score whereby a prediction ofthe risk of Torsades de Pointes in clinical use may be made based on themedications propensity to block I_(Kr)/hERG, the effective therapeuticplasma concentration (ETPC_(unbound)), and electrophysiological data. Inanother study, various ion channel effects (Multiple Ion Channel Effects(MICE)) were viewed. After comparing the various models which includedI_(Kr), I_(Na), and I_(Ca), the study concluded that the best MICE modelonly required taking into account the medication's effects onI_(Kr)/hERG and I_(Ca).

Medications that show a QT prolongation of less than 10 millisecondsgenerally are not a cause for concern regarding QT-related safety. Forexample, moxifloxacin is generally considered a positive control forproducing QT prolongation, with a range of 7-10 milliseconds added tothe QTc interval. However, it should be noted that while a medicationadministered on its own may not show evidence of QT prolongation, underconditions of drug-drug interactions, where the drugs metabolism isimpaired, it may exhibit significant levels of QT prolongation, such isthe case with terfenadine. Thus, even small increases in QTc uponadministration of a given medication should be regarded with caution.

Existence of Pharmacokinetic and Pharmacodynamic Interactions. Whenmetabolism is inhibited, medications will have higher concentrationsthroughout the body, including in the heart. A study found that roughly35% of 249 patients experiencing Torsades de Pointes from non-cardiacdrugs had a potential metabolic interaction. A patient's renal functionshould be considered since exemplary medications like sotalol anddofetilide are primarily eliminated by the kidneys and will haveincreasing concentrations in proportion to loss of kidney function.Furthermore, over-the-counter medications (OTCs) should be evaluated,including products like cimetidine and grapefruit juice, to get anaccurate picture of a patient's metabolizing enzyme functionality.

Another study examined the drug-drug interaction alerts for potentialrisk of QTc prolongation. The study found that out of the patients whohad an ECG before and after initiation of the interacting drugs, 31% hadQTc prolongation to the extent that they were considered at risk forTorsades de Pointes. The average increase in QTc duration was 31milliseconds. Giving the prescriber the ability to override the alertunfortunately did not result in subsequent recording of ECGs.

Existence of Non-Modifiable Risk Factors. Genetic risk factors have beenstudied by numerous groups and in a few large studies, but they havelacked specific and substantial evidence to demonstrate the role ofgenetics in drug-induced LQTS. The genetic variant with the mostevidence for affecting drug-induced LQTS is the KCNE1 mutation D85N,which impacts I_(Ks) function. The odds ratio of having this unfavorablemutation is between 9 and 12. Another study found that the KCNE1 D85Nmutation predicted drug-induced LQTS with an odds ratio of 9.0 (95%confidence interval=3.5−22.9). This study looked at diLQTS cases in aEuropean population, where population controls were all from Germany.

Existence of Co-Morbidities that May Have an Effect on QTc Interval.Patients with heart failure and left ventricular hypertrophy have anup-regulation of Ca²⁺ channels and a down-regulation of K⁺ channels,which may contribute to prolonged action potential duration, thusprolonged QT interval. In heart failure, the I_(to) current is reducedand adverse effects on other mechanisms of repoloarization may be morepronounced.

Another study reported that QTc prolongation was associated with avariety of clinical conditions including: congestive heart failure,ischemic cardiopathy, diabetes, renal failure, arrhythmias,hypothyroidism, and bradycardia. Patients with diabetes are at risk ofTorsades de Pointes due to CV complications, nephropathy, acidosis thataffects electrolyte balance, and polypharmacy. For example, PI3Ksignaling is decreased in mouse models of diabetes, which may alterI_(Kr) trafficking to the membrane.

Situations that may precipitate electrolyte disturbances may be apreliminary indicator of risk, such as severe dieting or eatingdisorders, depressed/mentally ill patients, acidosis (e.g., in patientswith diabetes), and renal insufficiency.

Method of Determining a Patient-Specific LOTS Score

While the medication-specific risk index may be helpful whenscrutinizing a single medication, the reality is that certain patientstake many medications and may have individual risk factors that maypredispose or protect them from QT prolongation and Torsades de Pointes.

In some embodiments, the invention described herein includes a methodfor identifying a patient-specific LQTS score that is dynamic and basedon a patient's current condition and medication regimen. The riskfactors described herein are included based on the evidence above, andare assigned points as follows with the points determined by theassociated methods illustrated in FIGS. 2 to 9 and describedhereinbelow:

Risk Points Point Determination Factor Description Range Method 1 Maleor female gender, also includes age for males 0-0.5 FIG. 2 2 HeartRhythm: sinus rhythm, Atrial Fibrillation, Sick Sinus 0-1   FIG. 3Syndrome, Pause, Heart Rate, Beta-blocker usage 3 Hypokalemia (K < 3.5mEq/L); use of triamterene 0-1   FIG. 4 4 Hypomagnesemia (Mg < 1.5mEq/L) 0-1   FIG. 5 5 Diuretics 0-1   FIG. 6 6 Antiarrhythmics: ClassIA, Class IC, Class III; amiodarone 0-9   FIG. 7 7 QT-prolonging drugsand drug interactions 0-12  FIG. 8 8 QTc interval (Cut-offs: <450, <475,<500, <550, 550+ msec) 0-10  FIG. 9

In an exemplary embodiment, the points associated with risk factors 1through 8 are added, where a sum of 10 or greater may indicate anincreased risk of Torsades de Pointes.

The aforementioned model and scoring mechanism has been validatedagainst literature cases of Torsades de Pointes. As described herein,more than 50 cases of documented Torsades de Pointes due to medicationuse and/or medication interactions have been identified andcorresponding risk scores have been calculated based on the methodsdescribed herein. In these cases, the risk scores are generally above10.

Point Determination Methods Associated with Each Risk Factor

As described herein, the methods for determining a patient-specificscore may be based on an examination of eight risk factors. The riskfactors may be represented by values or points, which are determinedaccording to the following methods.

Although eight risk factors may be examined, in some embodiments,examination of one or more risk factors may provide evidence of apatient's risk of developing long QT syndrome or Torsades de Pointes. Insome embodiments, examination of two or more risk factors may provideevidence of a patient's risk of developing long QT syndrome or Torsadesde Pointes. In some embodiments, examination of three or more riskfactors may provide evidence of a patient's risk of developing long QTsyndrome or Torsades de Pointes. In some embodiments, examination offour or more risk factors may provide evidence of a patient's risk ofdeveloping long QT syndrome or Torsades de Pointes. In some embodiments,examination of five or more risk factors may provide evidence of apatient's risk of developing long QT syndrome or Torsades de Pointes. Insome embodiments, examination of six or more risk factors may provideevidence of a patient's risk of developing long QT syndrome or Torsadesde Pointes. In some embodiments, examination of seven or more riskfactors may provide evidence of a patient's risk of developing long QTsyndrome or Torsades de Pointes.

In some embodiments, patient symptoms and/or analyte levels (e.g.,magnesium and potassium levels) may be measured from samples taken fromthe respective patient or recorded from the patient (e.g., by recordinga patient's heart rhythm), as is generally known in the art. Forexample, analyte levels (e.g., levels of magnesium, potassium,diuretics, antiarrhythmics, and/or QT-prolonging drug levels) may beanalyzed and/or or measured by techniques generally known in the artfrom a bodily fluid sample procured from the patient. In someembodiments, the bodily fluid may include, without limitation, saliva,blood, serum, or urine.

Risk Factor 1

In an embodiment, risk factor 1 may represent a value of 0 to 0.5. isthe evaluation of risk factor 1 is illustrated in FIG. 2 and describedbelow.

In an embodiment, where a patient is female, the value of risk factor 1may be 0.5. A QT interval is 10-15 milliseconds longer in women than inmen throughout their life span. Generally, QTc should be shorter than460 milliseconds in women. Indeed, QTc should be shorter than 450milliseconds in men and shorter than 460 milliseconds in women.

In an embodiment, where a patient is male and greater than 65 years ofage, the value of risk factor 1 may be 0.5. A QT interval increases10-15 milliseconds over time in men.

In an embodiment, where a patient is male and less than 65 years of age,the value of risk factor 1 may be 0.

Risk Factor 2

In an embodiment, risk factor 2 may represent a value of 0 to 1. Theevaluation of risk factor 2 is illustrated in FIG. 3 and describedbelow.

In an embodiment, where a patient's heart rhythm is unknown and thepatient is taking a beta-blocker, the value of risk factor 2 is 0. Ifthe patient LQTS score is greater than or equal to 3, the patient'sheart rate value and ECG should be obtained, if possible.

In an embodiment, where a patient's heart rhythm is unknown and thepatient not taking a beta-blocker, the value of risk factor 2 is 0.

In an embodiment, where a patient has a regular sinus rhythm at rest anda heart rate of 50 bpm or greater, the value of risk factor 2 is 0.

In an embodiment, where a patient has a regular sinus rhythm at rest,but is not taking a beta blocker, the value of risk factor 2 is 1.

In an embodiment, where a patient has a regular sinus rhythm at rest andis taking a beta blocker, the value of risk factor 2 is 0.5.

In an embodiment, where a patient has a regular sinus rhythm at rest,but does not have a heart rate of 50 bpm or greater, and is not taking abeta-blocker, the value of risk factor 2 is 1. A heart rate less than 50bpm is associated with a QT interval of 450 milliseconds or greater.

In an embodiment, where a patient has a regular sinus rhythm at rest,but does not have a heart rate of 50 bpm or greater, and is taking abeta-blocker, the value of risk factor 2 is 0.5. The dose of the betablocker should be reviewed if the patient's heart rate is less than 50bpm. A heart rate less than 50 bpm is normally associated with a QT of450 milliseconds or greater.

In an embodiment, where a patient does not have a regular sinus rhythmat rest and has atrial fibrillation, the value of risk factor 2 is 0.5.Atrial fibrillation is intrinsically associated with a decreased risk ofLQTS. However, under conditions of AV block and upon AF relapse andreturn to sinus rhythm, chances of pause and a long cardiac cycleincrease the risk of LQTS.

In an embodiment, where a patient does not have a regular sinus rhythmat rest and does not have atrial fibrillation, but has sick sinussyndrome or pause, then the value of risk factor 2 is 1. Patients withsyncope or sick sinus syndrome are at increased risk of short-long-shortcycles triggering Torsades de Pointes. Patients with a pacemaker areprotected as long as the device remains functional.

In an embodiment, where a patient does not have a regular sinus rhythmat rest and does not have atrial fibrillation, the value of risk factor2 is 0.

In an embodiment, where a patient does not have a regular sinus rhythmat rest and does not have sick sinus syndrome or pause, the value ofrisk factor 2 is 0.

In an embodiment, where a patient does not have a regular sinus rhythmat rest and does not have sick sinus syndrome or pause, the value ofrisk factor 2 is 0.

Risk Factor 3

In an embodiment, risk factor 3 may represent a value of 0 to 1. Theevaluation of risk factor 3 is illustrated in FIG. 4 and describedbelow.

In an embodiment, where a patient has an LQTS score of 3 or greater, thepatient's potassium levels should be tested and an ECG should beperformed, if possible.

In an embodiment, where a patient has a potassium level of 3.5 mEq/L orgreater and is not taking triamterene, the value of risk factor 3 is 0.

In an embodiment, where a patient has a potassium level of 3.5 mEq/L orgreater and is taking triamterene, the value of risk factor 3 is 0.5.Although triamterene can prevent hypokalemia, the drug has beenassociated with significance block of k_(r) current. Cases of prolongedQT interval have been reported.

In an embodiment, where a patient does not have a potassium level of 3.5mEq/L or greater, the value of risk factor 3 is 1. The underlying causesof hypokalemia should be addressed as the magnitude of potassium currentinvolved in the cardiac repolarization is decreased and block ofpotassium channels is increased by low extracellular potassium levels.Diuretic use should be avoided or re-evaluated.

Risk Factor 4

In an embodiment, risk factor 4 may represent a value of 0 to 1. Theevaluation of risk factor 4 is illustrated in FIG. 5 and describedbelow.

In an embodiment, where a patient has an LQTS score of 3 or greater, thepatient's magnesium levels should be tested and an ECG should beperformed, if possible.

In an embodiment, where a patient has a magnesium level of 1.5 mEq/L orgreater, the value of risk factor 4 is 0.

In an embodiment, where a patient does not have a magnesium level of 1.5mEq/L or greater, the value of risk factor 4 is 1. The underlying causesof hypomagnesemia should be addressed as potassium channel selectivityand function are altered under conditions of low magnesiumconcentrations. Diuretic use should be avoided or re-evaluated.Magnesium infusion may be useful to reverse Torsades de Pointes.

Risk Factor 5

In an embodiment, risk factor 5 may represent a value of 0 to 1. Theevaluation of risk factor 5 is illustrated in FIG. 6 and describedbelow.

In an embodiment, where a patient is not taking a thiazide-likediuretic, the value of risk factor 5 is 0.

In an embodiment, where a patient is taking a thiazide-like diuretic andis taking indapamide, the value of risk factor 5 is 1. Indapamide hasbeen associated with cases of Torsades de Pointes in patients withnormal potassium levels. Indapamide blocks I_(KS), the “reservecurrent,” for repolarization of human ventricular myocytes.

In an embodiment, where a patient is taking a thiazide-like diuretic andis not taking indapamide, but is taking hydro-chlorothiazide, then thevalue of risk factor 5 is 0. In such an instance, potassium levels inthe patient should be monitored. If a patient's LQTS score is 6 orgreater, hydro-chlorothiazide use by the patient should be discontinued.

In an embodiment, where a patient is taking a thiazide-like diuretic andis not taking indapamide or hydro-chlorothiazide or chlorthalidone, thenthe value of risk factor 5 is 0.

In an embodiment, where a patient is taking a thiazide-like diuretic andis not taking indapamide or hydro-chlorothiazide, but is takingchlorthalidone, then the value of risk factor 5 is 0. In such aninstance, potassium levels in the patient should be monitored. If apatient's LQTS score is 6 or greater, hydro-chlorothiazide use by thepatient should be discontinued.

Risk Factor 6

In an embodiment, risk factor 6 may represent a value of 0 to 9. Theevaluation of risk factor 6 is illustrated in FIG. 7 and describedbelow.

In an embodiment, where a patient is not taking a class IIIantiarrhythmic (AA), but is taking both a Class IA AA and a Class IC AA,then the value of risk factor 6 is 5. Treatment with both Class IA andIC AAs has been associated with cases of LQTS and Torsades de Pointes.Medication risk mitigation strategies should be used to limit other riskfactors of drug-induced LQTS.

In an embodiment, where a patient is not taking a class III AA, but istaking a class IA AA and is not taking a class IC AA, then the value ofrisk factor 6 is 4. Treatment with class IA AAs has been associated withcases of LQTS and Torsades de Pointes. A medication risk mitigationstrategy should be used to limit other risk factors of drug-inducedLQTS.

In an embodiment, where a patient is not taking a class III AA, a classIA AA, or a class IC AA, then the value of risk factor 6 is 0.

In an embodiment, where a patient is not taking a class III AA and isnot taking a class IA AA, but is taking a class IC AA, then the value ofrisk factor 6 is 2. Treatment with class IC AAs has been associated withcases of LQTS and Torsades de Pointes. A medication risk mitigationstrategy should be used to limit other risk factors of drug-inducedLQTS.

In an embodiment, where a patient is taking a class III AA and is takingamiodarone and a class IA AA, then the value of risk factor 6 is 7. Thecombined use of amiodarone with a class IA AA may put a patient at greatrisk of LQTS and Torsades de Pointes. A medication risk mitigationstrategy should be used to limit other risk factors of drug-inducedLQTS.

In an embodiment, where a patient is taking a class III AA and is takingamiodarone, but is not taking a class IA AA and is not taking a class ICAA, then the value of risk factor 6 is 3. Amiodarone use has beenassociated with cases of LQTS and Torsades de Pointes. A medication riskmitigation strategy should be used to limit other risk factors ofdrug-induced LQTS.

In an embodiment, where a patient is taking a class III AA and is takingamiodarone, but is not taking a class IA AA and is taking a class IC AA,then the value of risk factor 6 is 5. The combined use of amiodaronewith a class IC AA may put a patient at great risk of LQTS and Torsadesde Pointes. A medication risk mitigation strategy should be used tolimit other risk factors of drug-induced LQTS.

In an embodiment, where a patient is taking a class III AA and is nottaking amiodarone, but is taking a class IA AA, then the value of riskfactor 6 is 9. The combined use of class III and class IA AAs may put apatient at great risk of LQTS and Torsades de Pointes. Their use incombination should be reconsidered. A medication risk mitigationstrategy should be used to limit other factors of drug-induced LQTS.

In an embodiment, where a patient is taking a class III AA and is nottaking amiodarone or a class IA AA, but is taking a class IC AA, thenthe value of risk factor 6 is 7. The combined use of class III and classIA AAs may put a patient at great risk of LQTS and Torsades de Pointes.Their use in combination should be reconsidered. A medication riskstrategy should be used to limit other factors of drug-induced LQTS.

In an embodiment, where a patient is taking a class III AA and is nottaking amiodarone, a class IA AA, or a class IC AA, then the value ofrisk factor 6 is 5. Class III AAs prolong the action potential durationand have been associated with cases of LQTS and Torsades de Pointes. Amedication risk strategy should be used to limit other factors ofdrug-induced LQTS.

Risk Factor 7

In an embodiment, risk factor 7 may represent a value of 0 to 12. Theevaluation of risk factor 7 is illustrated in FIG. 8 and described inthe table below.

Lengthy table referenced here US20210140944A1-20210513-T00001 Pleaserefer to the end of the specification for access instructions.

Risk Factor 8

In an embodiment, risk factor 8 may represent a value of 0 to 10. Theevaluation of risk factor 8 is illustrated in FIG. 9 and describedbelow.

In an embodiment, where a patient does not have a QTc of greater than orequal to 450 milliseconds, the value of risk factor 8 is 0.

In an embodiment, where a patient has a QTc of between 450 millisecondsand 475 milliseconds, the value of risk factor 8 is 1. In someembodiments, a QTc interval of between 450 milliseconds and 475milliseconds is associated with an increased risk of Torsades dePointes. The factors explaining QT prolongation should be investigated.

In an embodiment, where a patient has a QTc of between 475 millisecondsand 500 milliseconds, the value of risk factor 8 is 3. In someembodiments, a QTc interval of between 475 milliseconds and 500milliseconds is associated with a high risk of Torsades de Pointes. Thefactors explaining QT prolongation should be investigated.

In an embodiment, where a patient has a QTc of between 500 millisecondsand 550 milliseconds, the value of risk factor 8 is 6. In someembodiments, a QTc interval of between 500 milliseconds and 550milliseconds is associated with a very high risk of Torsades de Pointes.The factors explaining QT prolongation should be investigated.

In an embodiment, where a patient has a QTc of 550 milliseconds orgreater, the value of risk factor 8 is 10. In some embodiments, a QTcinterval greater than 550 milliseconds is associated with an extremelyhigh risk of Torsades de Pointes. The factors explaining QT prolongationshould be investigated.

Listing of Compounds Known to Contribute to LQTS

In some embodiments, compounds that may trigger a prolongation ofmyocardial repolarization time or otherwise contribute to LQTS (i.e.,LQTS/TdP Triggers) in a patient may include, without limitation,Albuterol, Alfuzosin, Amantadine, Amiodarone, Amitriptyline,Amphetamine, Arsenic trioxide, Astemizole, Atazanavir, Atomoxetine,Azithromycin, Bepridil, Chloral hydrate, Chloroquine, Chlorpromazine,Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clomipramine,Clozapine, Cocaine, Desipramine, Dexmethylphenidate, Diphenhydramine,Diphenhydramine, Disopyramide, Dobutamine, Dofetilide, Dolasetron,Domperidone, Dopamine, Doxepin, Dronedarone, Droperidol, Ephedrine,Epinephrine, Erythromycin, Escitalopram, Escitalopram, Famotidine,Felbamate, Fenfluramine, Flecamide, Fluconazole, Fluoxetine, Foscarnet,Fosphenyloin, Galantamine, Gatifloxacin, Gemifloxacin, Granisetron,Halofantrine, Haloperidol, Ibutilide, Imipramine, Indapamide,Isoproterenol, Isoproterenol, Isradipine, Itraconazole, Ketoconazole,Lapatinib, Lapatinib, Levalbuterol, Levofloxacin, Levomethadyl,Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol, Methadone,Methylphenidate, Midodrine, Moexipril/HCTZ, Moxifloxacin, Nicardipine,Nilotinib, Norepinephrine, Nortriptyline, Octreotide, Ofloxacin,Ondansetron, Oxytocin, Paliperidone, Paroxetine, Pentamidine, Perflutrenlipid microspheres, Phentermine, Phenylephrine, Phenylpropanolamine,Pimozide, Probucol, Procainamide, Protriptyline, Pseudoephedrine,Quetiapine, Quinidine, Ranolazine, Risperidone, Ritodrine, Ritonavir,Roxithromycin, Salmeterol, Sertindole, Sertraline, Sibutramine,Solifenacin, Sotalol, Sparfloxacin, Sunitinib, Tacrolimus, Tamoxifen,Telithromycin, Terbutaline, Terfenadine, Thioridazine, Tizanidine,Tolterodine, Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib,Vardenafil, Venlafaxine, Voriconazole, or Ziprasidone and thepharmaceutically acceptable salts thereof.

In some embodiments, LQTS/TdP Triggers may include, without limitation,class IA antiarrhythmics, class IC antiarrhythmics, or class IIIantiarrhythmics and the pharmaceutically acceptable salts thereof.

Listing of Compounds Used in the Treatment of LQTS

In some embodiments, one or more compounds may be provided for thetreatment of Long QT Syndrome and/or Torsades de Pointes (i.e., LQTSMedicaments or TdP Medicaments) upon a determination that a patient isidentified as having a high risk of Long QT Syndrome and/or Torsades dePointes. In some embodiments, such one or more compounds may include,but are not limited to potassium and/or magnesium.

In some embodiments, such one or more compounds used in the treatment ofLong QT Syndrome and/or Torsades de Pointes may include potassium suchas in the form of a potassium salt (e.g., KC1).

In some embodiments, such one or more compounds used in the treatment ofLong QT Syndrome and/or Torsades de Pointes may include magnesium suchas in the form of a magnesium salt (e.g., MgSO₄). For example, amagnesium sulfate infusion may be administered as an IV bolus (e.g., a 2gram bolus), which may be followed by an IV infusion of magnesium at arate of 2-4 mg per minute.

In some embodiments, such one or more compounds used in the treatment ofLong QT Syndrome and/or Torsades de Pointes may include a compounddescribed in U.S. Pat. Nos. 8,183,284, 8,658,358, 8,753,674, 8,987,262,9,126,989, 9,447,027, or 9,597,302, the entirety of which areincorporated herein by reference.

Pharmaceutical Compositions

In some embodiments, the invention includes a pharmaceutical compositionfor use in the treatment of the diseases and conditions describedherein. In some embodiments, the invention includes a pharmaceuticalcomposition comprising one or more LQTS/TdP Triggers, or apharmaceutically acceptable salt thereof. In some embodiments, theinvention includes one or more LQTS Medicaments, or a pharmaceuticallyacceptable salt thereof.

Where desired, the pharmaceutical compositions contain apharmaceutically acceptable salt and/or coordination complex of one ormore of the active ingredients. Typically, the pharmaceuticalcompositions also comprise one or more pharmaceutically acceptableexcipients, carriers, including inert solid diluents and fillers,diluents, including sterile aqueous solution and various organicsolvents, permeation enhancers, solubilizers and adjuvants.

The pharmaceutical compositions described above that include LQTSMedicaments are preferably for use in the treatment of the LQTS and/orTorsades de Pointes.

Where desired, other active pharmaceutical ingredient(s) may be mixedinto a preparation or two or more components of the combination may beformulated into separate preparations for use in combination separatelyor at the same time. A kit containing the components of the combination,formulated into separate preparations for said use, in also provided bythe invention.

In some embodiments, the concentration of any LQTS/TdP Trigger or LQTSMedicament provided in the pharmaceutical compositions of the inventionis independently less than, for example, 100%, 90%, 80%, 70%, 60%, 50%,40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%,7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%,0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%,0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%,0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/vor v/v of the pharmaceutical composition.

In some embodiments, the concentration of any LQTS/TdP Trigger or LQTSMedicament provided in the pharmaceutical compositions of the inventionis independently greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%,17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%,14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%,12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%,9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%,6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%,3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%,1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%,0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%,0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v, or v/v of thepharmaceutical composition.

In some embodiments, the concentration of any LQTS/TdP Trigger or LQTSMedicament provided in the pharmaceutical compositions is independentlyin the range from about 0.0001% to about 50%, about 0.001% to about 40%,about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% toabout 25%, about 0.07% to about 24%, about 0.08% to about 23%, about0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%,about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% toabout 14%, about 0.9% to about 12% or about 1% to about 10% w/w, w/v orv/v of the pharmaceutical composition.

In some embodiments, the concentration of any LQTS/TdP Trigger or LQTSMedicament provided in the pharmaceutical compositions is independentlyin the range from about 0.001% to about 10%, about 0.01% to about 5%,about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% toabout 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1%to about 0.9% w/w, w/v or v/v of the pharmaceutical composition.

In some embodiments, the amount of any LQTS/TdP Trigger or LQTSMedicament provided in the pharmaceutical compositions is independentlyequal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g,6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g,1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g,0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g,0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g,0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g,0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

In some embodiments, the amount of any LQTS/TdP Trigger or LQTSMedicament provided in the pharmaceutical compositions is independentlymore than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g,0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g,0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g,0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g,0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g,0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g,7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

Each of the LQTS/TdP Triggers or LQTS Medicaments according to theinvention is effective over a wide dosage range. For example, in thetreatment of adult humans, dosages independently ranging from 0.01 to1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40mg per day are examples of dosages that may be used. The exact dosagewill depend upon the route of administration, the form in which thecompound is administered, the gender and age of the subject to betreated, the body weight of the subject to be treated, and thepreference and experience of the attending physician.

Described below are non-limiting pharmaceutical compositions and methodsfor preparing the same.

Pharmaceutical Compositions for Oral Administration

In certain embodiments, the invention provides a pharmaceuticalcomposition for oral administration containing one or more LQTS/TdPTriggers or LQTS Medicaments, and a pharmaceutical excipient suitablefor administration.

In certain embodiments, the invention provides a solid pharmaceuticalcomposition for oral administration containing: (i) an effective amountof one or more LQTS/TdP Triggers or LQTS Medicaments and (ii) apharmaceutical excipient suitable for administration.

In some embodiments, the pharmaceutical composition may be a liquidpharmaceutical composition suitable for oral consumption.

Pharmaceutical compositions of the invention suitable for oraladministration can be presented as discrete dosage forms, such ascapsules, sachets, tablets, liquids, or aerosol sprays each containing apredetermined amount of an active ingredient as a powder or in granules,a solution, or a suspension in an aqueous or non-aqueous liquid, anoil-in-water emulsion, a water-in-oil liquid emulsion, powders forreconstitution, powders for oral consumptions, bottles (includingpowders or liquids in a bottle), orally dissolving films, lozenges,pastes, tubes, gums, and packs. Such dosage forms can be prepared by anyof the methods of pharmacy, but all methods include the step of bringingthe active ingredient(s) into association with the carrier, whichconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient(s) with liquid carriers or finely divided solidcarriers or both, and then, if necessary, shaping the product into thedesired presentation. For example, a tablet can be prepared bycompression or molding, optionally with one or more accessoryingredients. Compressed tablets can be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such aspowder or granules, optionally mixed with an excipient such as, but notlimited to, a binder, a lubricant, an inert diluent, and/or a surfaceactive or dispersing agent. Molded tablets can be made by molding in asuitable machine a mixture of the powdered compound moistened with aninert liquid diluent.

The invention further encompasses anhydrous pharmaceutical compositionsand dosage forms since water can facilitate the degradation of somecompounds. For example, water may be added (e.g., 5%) in thepharmaceutical arts as a means of simulating long-term storage in orderto determine characteristics such as shelf-life or the stability offormulations over time. Anhydrous pharmaceutical compositions and dosageforms of the invention can be prepared using anhydrous or low moisturecontaining ingredients and low moisture or low humidity conditions.Pharmaceutical compositions and dosage forms of the invention whichcontain lactose can be made anhydrous if substantial contact withmoisture and/or humidity during manufacturing, packaging, and/or storageis expected. An anhydrous pharmaceutical composition may be prepared andstored such that its anhydrous nature is maintained. Accordingly,anhydrous compositions may be packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

Each of the one or more LQTS/TdP Triggers or LQTS Medicaments as activeingredients can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the compositions for an oral dosage form, any of the usualpharmaceutical media can be employed as carriers, such as, for example,water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, and the like in the case of oral liquid preparations(such as suspensions, solutions, and elixirs) or aerosols; or carrierssuch as starches, sugars, micro-crystalline cellulose, diluents,granulating agents, lubricants, binders, and disintegrating agents canbe used in the case of oral solid preparations, in some embodimentswithout employing the use of lactose. For example, suitable carriersinclude powders, capsules, and tablets, with the solid oralpreparations. If desired, tablets can be coated by standard aqueous ornonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions of the invention toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant may produce tablets whichdisintegrate in the bottle. Too little may be insufficient fordisintegration to occur, thus altering the rate and extent of release ofthe active ingredients from the dosage form. Thus, a sufficient amountof disintegrant that is neither too little nor too much to detrimentallyalter the release of the active ingredient(s) may be used to form thedosage forms of the compounds disclosed herein. The amount ofdisintegrant used may vary based upon the type of formulation and modeof administration, and may be readily discernible to those of ordinaryskill in the art. About 0.5 to about 15 weight percent of disintegrant,or about 1 to about 5 weight percent of disintegrant, may be used in thepharmaceutical composition. Disintegrants that can be used to formpharmaceutical compositions and dosage forms of the invention include,but are not limited to, agar-agar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,other starches, pre-gelatinized starch, other starches, clays, otheralgins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, sodium stearyl fumarate, mineral oil,light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol,other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenatedvegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesameoil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate,ethylaureate, agar, or mixtures thereof. Additional lubricants include,for example, a syloid silica gel, a coagulated aerosol of syntheticsilica, silicified microcrystalline cellulose, or mixtures thereof. Alubricant can optionally be added in an amount of less than about 0.5%or less than about 1% (by weight) of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active pharmaceutical ingredient(s) may be combinedwith various sweetening or flavoring agents, coloring matter or dyesand, if so desired, emulsifying and/or suspending agents, together withsuch diluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,hydrophilic surfactants, lipophilic surfactants, and mixtures thereof.That is, a mixture of hydrophilic surfactants may be employed, a mixtureof lipophilic surfactants may be employed, or a mixture of at least onehydrophilic surfactant and at least one lipophilic surfactant may beemployed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions. Hydrophilic surfactants are generally considered tobe those compounds having an HLB value greater than about 10, as well asanionic, cationic, or zwitterionic compounds for which the HLB scale isnot generally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are compounds having an HLB value equal to or less thanabout 10. However, HLB value of a surfactant is merely a rough guidegenerally used to enable formulation of industrial, pharmaceutical andcosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof,carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acylactylates; mono- and di-acetylated tartaricacid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylenesterols, derivatives, and analogues thereof; polyoxyethylated vitaminsand derivatives thereof; polyoxyethylene-polyoxypropylene blockcopolymers; and mixtures thereof; polyethylene glycol sorbitan fattyacid esters and hydrophilic transesterification products of a polyolwith at least one member of the group consisting of triglycerides,vegetable oils, and hydrogenated vegetable oils. The polyol may beglycerol, ethylene glycol, polyethylene glycol, sorbitol, propyleneglycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-101aurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,polyglyceryl-10-oleate, Tween 40, Tween 60, sucrose monostearate,sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenolseries, PEG 15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols; oil-solublevitamins/vitamin derivatives; and mixtures thereof. Within this group,preferred lipophilic surfactants include glycerol fatty acid esters,propylene glycol fatty acid esters, and mixtures thereof, or arehydrophobic transesterification products of a polyol with at least onemember of the group consisting of vegetable oils, hydrogenated vegetableoils, and triglycerides.

In an embodiment, the composition may include a solubilizer to ensuregood solubilization and/or dissolution of the compound of the presentinvention and to minimize precipitation of the compound of the presentinvention. This can be especially important for compositions fornon-oral use—e.g., compositions for injection. A solubilizer may also beadded to increase the solubility of the hydrophilic drug and/or othercomponents, such as surfactants, or to maintain the composition as astable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, F-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. Particularlypreferred solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer may be limited to abioacceptable amount, which may be readily determined by one of skill inthe art. In some circumstances, it may be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the composition to a patientusing conventional techniques, such as distillation or evaporation.Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%,50%, 100%, or up to about 200% by weight, based on the combined weightof the drug, and other excipients. If desired, very small amounts ofsolubilizer may also be used, such as 5%, 2%, 1% or even less.Typically, the solubilizer may be present in an amount of about 1% toabout 100%, more typically about 5% to about 25% by weight.

The composition can further include one or more pharmaceuticallyacceptable additives and excipients. Such additives and excipientsinclude, without limitation, detackifiers, anti-foaming agents,buffering agents, polymers, antioxidants, preservatives, chelatingagents, viscomodulators, tonicifiers, flavorants, colorants, odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, and mixtures thereof

In addition, an acid or a base may be incorporated into the compositionto facilitate processing, to enhance stability, or for other reasons.Examples of pharmaceutically acceptable bases include amino acids, aminoacid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide,sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate,magnesium hydroxide, magnesium aluminum silicate, synthetic aluminumsilicate, synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable arebases that are salts of a pharmaceutically acceptable acid, such asacetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonicacid, uric acid, and the like. Salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphatecan also be used. When the base is a salt, the cation can be anyconvenient and pharmaceutically acceptable cation, such as ammonium,alkali metals and alkaline earth metals. Example may include, but notlimited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid and uric acid.

Pharmaceutical Compositions for Injection

In certain embodiments, the invention provides a pharmaceuticalcomposition for injection containing the combination of one or moreLQTS/TdP Triggers or LQTS Medicaments, and a pharmaceutical excipientsuitable for injection. Components and amounts of agents in thecompositions are as described herein.

The forms in which the compositions of the present invention may beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (andsuitable mixtures thereof), cyclodextrin derivatives, and vegetable oilsmay also be employed. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, for the maintenanceof the required particle size in the case of dispersion and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.

Sterile injectable solutions are prepared by incorporating thecombination of the one or more LQTS/TdP Triggers or LQTS Medicaments inthe required amounts in the appropriate solvent with various otheringredients as enumerated above, as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating thevarious sterilized active ingredients into a sterile vehicle whichcontains the basic dispersion medium and the required other ingredientsfrom those enumerated above. In the case of sterile powders for thepreparation of sterile injectable solutions, certain desirable methodsof preparation are vacuum-drying and freeze-drying techniques whichyield a powder of the active ingredient plus any additional desiredingredient from a previously sterile-filtered solution thereof.

Pharmaceutical Compositions for Topical Delivery

In certain embodiments, the invention provides a pharmaceuticalcomposition for transdermal delivery containing the combination of oneor more LQTS/TdP Triggers or LQTS Medicaments, and a pharmaceuticalexcipient suitable for transdermal delivery.

Compositions of the present invention can be formulated intopreparations in solid, semi-solid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationmay provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the one or more LQTS/TdP Triggers or LQTS Medicaments incontrolled amounts, either with or without another active pharmaceuticalingredient.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252; 4,992,445 and 5,001,139. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Pharmaceutical Compositions for Inhalation

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner. Dry powder inhalers may also be used toprovide inhaled delivery of the compositions.

Other Pharmaceutical Compositions

Pharmaceutical compositions may also be prepared from compositionsdescribed herein and one or more pharmaceutically acceptable excipientssuitable for sublingual, buccal, rectal, intraosseous, intraocular,intranasal, epidural, or intraspinal administration. Preparations forsuch pharmaceutical compositions are well-known in the art. See, e.g.,Anderson, et al., eds., Handbook of Clinical Drug Data, Tenth Edition,McGraw-Hill, 2002; and Pratt and Taylor, eds., Principles of DrugAction, Third Edition, Churchill Livingston, N.Y., 1990, each of whichis incorporated by reference herein in its entirety.

Administration of the combination of one or more LQTS/TdP Triggers orLQTS Medicaments or pharmaceutical compositions of these compounds canbe effected by any method that enables delivery of the compounds to thesite of action. These methods include oral routes, intraduodenal routes,parenteral injection (including intravenous, intraarterial,subcutaneous, intramuscular, intravascular, intraperitoneal orinfusion), topical (e.g., transdermal application), rectaladministration, via local delivery by catheter or stent or throughinhalation. The combination of compounds can also be administeredintraadiposally or intrathecally.

The compositions of the invention may also be delivered via animpregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer. Such a method of administrationmay, for example, aid in the prevention or amelioration of restenosisfollowing procedures such as balloon angioplasty. Without being bound bytheory, compounds of the invention may slow or inhibit the migration andproliferation of smooth muscle cells in the arterial wall whichcontribute to restenosis. A compound of the invention may beadministered, for example, by local delivery from the struts of a stent,from a stent graft, from grafts, or from the cover or sheath of a stent.In some embodiments, a compound of the invention is admixed with amatrix. Such a matrix may be a polymeric matrix, and may serve to bondthe compound to the stent. Polymeric matrices suitable for such use,include, for example, lactone-based polyesters or copolyesters such aspolylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides,polyaminoacids, polysaccharides, polyphosphazenes, poly(ether-ester)copolymers (e.g., PEO-PLLA); polydimethylsiloxane,poly(ethylene-vinylacetate), acrylate-based polymers or copolymers(e.g., polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone),fluorinated polymers such as polytetrafluoroethylene and celluloseesters. Suitable matrices may be nondegrading or may degrade with time,releasing the compound or compounds. The combination of the one or moreLQTS/TdP Triggers or LQTS Medicaments may be applied to the surface ofthe stent by various methods such as dip/spin coating, spray coating,dip-coating, and/or brush-coating. The compounds may be applied in asolvent and the solvent may be allowed to evaporate, thus forming alayer of compound onto the stent. Alternatively, the compound may belocated in the body of the stent or graft, for example in microchannelsor micropores. When implanted, the compound diffuses out of the body ofthe stent to contact the arterial wall. Such stents may be prepared bydipping a stent manufactured to contain such micropores or microchannelsinto a solution of the compound of the invention in a suitable solvent,followed by evaporation of the solvent. Excess drug on the surface ofthe stent may be removed via an additional brief solvent wash. In yetother embodiments, compounds of the invention may be covalently linkedto a stent or graft. A covalent linker may be used which degrades invivo, leading to the release of the compound of the invention. Anybio-labile linkage may be used for such a purpose, such as ester, amideor anhydride linkages.

Exemplary parenteral administration forms include solutions orsuspensions of active compound in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

The invention also provides kits. The kits include each of the one ormore LQTS/TdP Triggers or LQTS Medicaments, either alone or incombination in suitable packaging, and written material that can includeinstructions for use, discussion of clinical studies and listing of sideeffects. Such kits may also include information, such as scientificliterature references, package insert materials, clinical trial results,and/or summaries of these and the like, which indicate or establish theactivities and/or advantages of the composition, and/or which describedosing, administration, side effects, drug interactions, or otherinformation useful to the health care provider. Such information may bebased on the results of various studies, for example, studies usingexperimental animals involving in vivo models and studies based on humanclinical trials. The kit may further contain another activepharmaceutical ingredient. In some embodiments, the one or more LQTS/TdPTriggers or LQTS Medicaments and another active pharmaceuticalingredient are provided as separate compositions in separate containerswithin the kit. In some embodiments, the one or more LQTS/TdP Triggersor LQTS Medicaments and the agent are provided as a single compositionwithin a container in the kit. Suitable packaging and additionalarticles for use (e.g., measuring cup for liquid preparations, foilwrapping to minimize exposure to air, and the like) are known in the artand may be included in the kit. Kits described herein can be provided,marketed and/or promoted to health providers, including physicians,nurses, pharmacists, formulary officials, and the like. Kits may also,in some embodiments, be marketed directly to the consumer.

Dosages and Dosing Regimens

The amounts of the one or more LQTS/TdP Triggers or LQTS Medicamentsadministered will be dependent on the human or mammal being treated, theseverity of the disorder or condition, the rate of administration, thedisposition of the compounds and the discretion of the prescribingphysician. However, an effective dosage of each is in the range of about0.001 to about 100 mg per kg body weight per day, such as about 1 toabout 35 mg/kg/day, in single or divided doses. For a 70 kg human, thiswould amount to about 0.05 to 7 g/day, such as about 0.05 to about 2.5g/day. In some instances, dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful sideeffect—e.g., by dividing such larger doses into several small doses foradministration throughout the day. The dosage of one or more LQTS/TdPTriggers or LQTS Medicaments may be provided in units of mg/kg of bodymass or in mg/m² of body surface area.

Administration of the active pharmaceutical ingredients of the inventionmay continue as long as necessary. In some embodiments, the combinationof one or more LQTS/TdP Triggers or LQTS Medicaments is administered formore than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, thecombination of one or more LQTS/TdP Triggers or LQTS Medicaments isadministered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In someembodiments, the combination of one or more LQTS/TdP Triggers or LQTSMedicaments is administered chronically on an ongoing basis—e.g., forthe treatment of chronic effects. In another embodiment theadministration of the combination of the one or more LQTS/TdP Triggersor LQTS Medicaments continues for less than about 7 days. In yet anotherembodiment the administration continues for more than about 6, 10, 14,28 days, two months, six months, or one year. In some cases, continuousdosing is achieved and maintained as long as necessary.

In some embodiments, an effective dosage of a LQTS/TdP Trigger or LQTSMedicament disclosed herein is in the range of about 1 mg to about 500mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg, about 50mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg toabout 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about198 to about 202 mg. In some embodiments, an effective dosage of aLQTS/TdP Trigger or LQTS Medicament disclosed herein is about 25 mg,about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg,about 175 mg, about 200 mg, about 225 mg, or about 250 mg.

In some embodiments, an effective dosage of a LQTS/TdP Trigger or LQTSMedicament disclosed herein is in the range of about 0.01 mg/kg to about4.3 mg/kg, about 0.15 mg/kg to about 3.6 mg/kg, about 0.3 mg/kg to about3.2 mg/kg, about 0.35 mg/kg to about 2.85 mg/kg, about 0.15 mg/kg toabout 2.85 mg/kg, about 0.3 mg to about 2.15 mg/kg, about 0.45 mg/kg toabout 1.7 mg/kg, about 0.15 mg/kg to about 1.3 mg/kg, about 0.3 mg/kg toabout 1.15 mg/kg, about 0.45 mg/kg to about 1 mg/kg, about 0.55 mg/kg toabout 0.85 mg/kg, about 0.65 mg/kg to about 0.8 mg/kg, about 0.7 mg/kgto about 0.75 mg/kg, about 0.7 mg/kg to about 2.15 mg/kg, about 0.85mg/kg to about 2 mg/kg, about 1 mg/kg to about 1.85 mg/kg, about 1.15mg/kg to about 1.7 mg/kg, about 1.3 mg/kg mg to about 1.6 mg/kg, about1.35 mg/kg to about 1.5 mg/kg, about 2.15 mg/kg to about 3.6 mg/kg,about 2.3 mg/kg to about 3.4 mg/kg, about 2.4 mg/kg to about 3.3 mg/kg,about 2.6 mg/kg to about 3.15 mg/kg, about 2.7 mg/kg to about 3 mg/kg,about 2.8 mg/kg to about 3 mg/kg, or about 2.85 mg/kg to about 2.95mg/kg. In some embodiments, an effective dosage of a LQTS/TdP Trigger orLQTS Medicament disclosed herein is about 0.35 mg/kg, about 0.7 mg/kg,about 1 mg/kg, about 1.4 mg/kg, about 1.8 mg/kg, about 2.1 mg/kg, about2.5 mg/kg, about 2.85 mg/kg, about 3.2 mg/kg, or about 3.6 mg/kg.

In some instances, dosage levels below the lower limit of the aforesaidranges may be more than adequate, while in other cases still largerdoses may be employed without causing any harmful side effect—e.g., bydividing such larger doses into several small doses for administrationthroughout the day.

An effective amount of the combination of one or more LQTS/TdP Triggersor LQTS Medicaments may be administered in either single or multipledoses by any of the accepted modes of administration of agents havingsimilar utilities, including rectal, buccal, intranasal and transdermalroutes, by intra-arterial injection, intravenously, intraperitoneally,parenterally, intramuscularly, subcutaneously, orally, topically, or asan inhalant.

Method of Treating a Patient Susceptible to LQTS

In an embodiment, the invention includes a method of treating patientswho are susceptible or at risk of developing long QT syndrome orTorsades de Pointes. In some embodiments, the method includes the stepof determining whether the patient has an increased risk of developinglong QT syndrome or Torsades de Pointes due to a patient-specific scoreof greater than 10. In some embodiments, where the patient specificscore is greater than 10, the method may include the step ofadministering a pharmaceutical composition to the patient comprising atherapeutically effective amount of an LQTS Medicament, and apharmaceutically acceptable carrier.

In an embodiment, the invention includes a method of treating patientswho may be susceptible or at risk of developing long QT syndrome orTorsades de Pointes. In some embodiments, the method includes the stepof determining whether the patient has an increased risk of developinglong QT syndrome or Torsades de Pointes due to a patient-specific scoreof greater than 10. In some embodiments, where the patient specificscore is greater than 10, the method may include the step ofadministering a pharmaceutical composition to the patient comprising atherapeutically effective amount of an LQTS Medicament, and apharmaceutically acceptable carrier. In some embodiments, where thepatient specific score is not greater than 10, the method may includethe step of step of administering a pharmaceutical composition to thepatient comprising a therapeutically effective amount of an LQTS/TdPTrigger, and a pharmaceutically acceptable carrier.

In an embodiment, the invention includes a method of treating patientshaving an increased risk of developing long QT syndrome or Torsades dePointes due to a patient-specific score of greater than 10. In someembodiments, the method may include the administration of atherapeutically effective amount of an LQTS Medicament, as describedherein.

In an embodiment, the invention includes a method of treating a patientwith an LQTS/TdP Trigger, which is determined to increase the risk oflong QT syndrome or Torsades de Pointes. In some embodiments, the methodmay include the step of confirming that the patient does not have anincreased risk of developing long QT syndrome or Torsades de Pointes dueto a patient-specific score of greater than 10. In some embodiments, themethod may include the step of administering a pharmaceuticalcomposition to the patient including a therapeutically effective amountof the LQTS/TdP Trigger, and a pharmaceutically acceptable carrier.

In an embodiment, the invention may include a method of treating apatient with an LQTS/TdP Trigger, which is determined to increase therisk of long QT syndrome or Torsades de Pointes, which may include thestep of administering a pharmaceutical composition to the patientincluding a therapeutically effective amount of the LQTS/TdP Trigger,and a pharmaceutically acceptable carrier. In some embodiments, themethod may include the step of determining whether the patient has anincreased risk of developing long QT syndrome or Torsades de Pointes duea patient-specific score that is indicative of an increased risk ofdeveloping long QT syndrome or Torsades de Pointes. In some embodiments,the patient-specific score that is indicative of an increased risk ofdeveloping long QT syndrome or Torsades de Pointes is greater than 10.In some embodiments, the method may further include halting treatment ofthe patient with the pharmaceutical composition. In some embodiments,the method may further include the administration of an additionalpharmaceutical composition to the patient that does not include theLQTS/TdP Trigger. In some embodiments, the additional pharmaceuticalcomposition includes an additional compound that has a drug-specificindex that is not less than 15. In some embodiments, the additionalpharmaceutical composition includes an additional compound that is anLQTS Medicament.

In some embodiments of the methods described herein, such methods mayinclude the step inserting a pacing catheter in the right ventricularchamber of the patient, wherein the pacing catheter may be attached toan external pacemaker.

In some embodiments of the methods described herein, such methods mayinclude the step of providing an Implantable Cardioverter Defribillator(ICD) at the patient or implanted in the patient to pace the hearthrhythm and prevent bradycardia, which may lead to an increased QTcinterval.

While preferred embodiments of the invention are shown and describedherein, such embodiments are provided by way of example only and are notintended to otherwise limit the scope of the invention. Variousalternatives to the described embodiments of the invention may beemployed in practicing the invention.

EXAMPLES

The embodiments encompassed herein are now described with reference tothe following examples. These examples are provided for the purpose ofillustration only and the disclosure encompassed herein should in no waybe construed as being limited to these examples, but rather should beconstrued to encompass any and all variations which become evident as aresult of the teachings provided herein.

Example 1—Validation of Drug-Specific LQTS Index with Terfenadine

Terfenadine is a non-sedating H1-antagonist that has been associatedwith several cases of QT prolongation and Torsades de Pointes, startingin the 90's. The drug was removed from the US market in January of 1997.Using pharmacological characteristics of terfenadine, the LQTS Index iscalculated, which may be described as the sum of K1+K2+K3−K4 (where K4is either a 0 or a subtraction of 5 from the sum of K1, K2, and K3).

Calculating LQTS index for terfenadine yields the following:

K1=(0.016*1000)/(3.18*((100−97)/100)*(381.6/127.20)*(100/5))

K2=0

K3=0

K4=0

The computed LQTS index for terfenadine is therefore 2.795. This valueis lower than the determined threshold for risk (15) and exemplifies adrug with high risk of QT prolongation and drug-induced Torsade dePointes.

Example 2—Validation of Long QT-JT Index for 155 Drugs

A drug specific LQTS index was calculated for 155 drugs as demonstratedin Example 1. The Z-score distribution of values obtained for each ofthese drugs was then plotted. Drugs were also categorized based onCredibleMeds characterization (www.crediblemeds.org) to either Highrisk, Conditional risk, Low risk, or Undetermined risk. A specificityand sensitivity analysis performed demonstrated that a threshold value15 was associated with maximum specificity and maximum sensitivity (seeFIG. 1).

Example 3—Evaluation of a Patient-Specific LQTS Score in an ExemplaryFemale Patient

An exemplary female patient with atrial fibrillation was being treatedwith sotalol (rhythm control of atrial fibrillation) and ciprofloxacin(urinary tract infection). Her potassium level was at 3.1 meq/L and shehad a measured QTc at 560 msec.

FIG. 10 illustrates an exemplary data input screen for calculating apatient-specific LQTS score and the results of such score are shownbelow where the patient in FIG. 10 has an LQTS Score of 19.

LQTS Analysis Result: A total LQTS Score of 19 was estimated for thispatient based on available information. This represents a precariouscondition, which requires immediate attention. However, the Total LQTSScore could be higher if all risk factors were taken into consideration.The missing risk factors are: (1) magnesium level; and (2) heart rate.

Risk Factor 1: 0.5. QT interval is 10-15 milliseconds longer in womenthan in men throughout their life span. QTc should be shorter than 450milliseconds in women.

Risk Factor 2: 0.5. Atrial fibrillation is intrinsically associated witha decreased risk of LQTS. However, under conditions of AV block and uponAF relapse and return to sinus rhythm, chances of pause and a longcardiac cycle increase the risk of LQTS.

Risk Factor 3: 1. Underlying causes of hypokalemia should be correctedas the magnitude of potassium currents involved in cardiacrepolarization is decreased and block of potassium channels is increasedby low extracellular potassium levels. Diuretic use should be avoided orre-evaluated.

Risk Factor 4: 0. Since the LQTS Score is greater than or equal to 4.5,magnesium levels should be obtained, if possible.

Risk Factor 5: 0.

Risk Factor 6: 5. Class III antiarrhythmics prolong the action potentialduration and have been associated with cases of LQTS and Torsades dePointes. Medication risk mitigation strategies should be used to limitother risk factors of drug induced LQTS.

Risk Factor 7: 2. Ciprofloxacin and Sotalol have been associated with aprolongation of the QT interval and Torsades de Pointes. Other riskfactors of drug-induced LQTS should be limited.

Risk Factor 8: 10. A QTc interval greater than 550 milliseconds isassociated with an extremely high risk of Torsades de Pointes. Allfactors explaining QT prolongation should be investigated.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20210140944A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A method for determining whether a compound is associated with anincreased risk of long QT syndrome or Torsades de Pointes by determininga drug-specific index, the method comprising the steps of: measuring afirst index variable comprising determining an IC₅₀ value for block ofone or more of I_(Kr) and I_(Ks), a Cmax of the compound at a test dose,a daily dose amount of the compound, a protein binding value for thecompound at a target protein, and a drug-drug interaction coefficient(DDIC) for the compound; measuring a second index variable comprisingdetermining an IC₅₀ value for block of CaV1.2 current, and the IC₅₀value for block of one or more of I_(Kr) and I_(Ks); measuring a thirdindex variable comprising determining an IC₅₀ value for block of NaV1.5current, and the IC₅₀ value for block of one or more of I_(Kr) andI_(Ks); measuring a fourth index variable comprising determining aqualitative value for the compound's inhibition of hERG trafficking; andcombining the first, second, third, and fourth index variables toprovide the drug-specific index, which is indicative of an increasedrisk of long QT syndrome or Torsades de Pointes.
 2. A method fordetermining whether a patient undergoing treatment with a compound hasan increased risk of long QT syndrome or Torsades de Pointes bydetermining a patient-specific score, the method comprising the stepsof: determining a risk variable based on the patient's gender and age;measuring the patient's heart rhythm comprising detecting one or more ofsinus rhythm, atrial fibrillation, sick sinus syndrome, pause, and heartrate; detecting a potassium level in the patient; detecting a magnesiumlevel in the patient; detecting the presence of one or more diuretics orantiarrhythmics in the patient; measuring a drug-specific index for oneor more drug therapeutics in the patient's treatment regimen; andmeasuring the patient's QT interval.
 3. A method of treating patientshaving an increased risk of developing long QT syndrome or Torsades dePointes due to a patient-specific score of greater than about 10, themethod comprising administering a therapeutically effective amount of acompound selected from the group consisting of a potassium salt and amagnesium salt.
 4. The method of claim 3, wherein the potassium saltcomprises potassium chloride.
 5. The method of claim 3, wherein themagnesium salt comprises magnesium sulfate.
 6. (canceled)
 7. The methodof claim 1, wherein the compound is selected from the group consistingof Albuterol, Alfuzosin, Amantadine, Amiodarone, Amitriptyline,Amphetamine, Arsenic trioxide, Astemizole, Atazanavir, Atomoxetine,Azithromycin, Bepridil, Chloral hydrate, Chloroquine, Chlorpromazine,Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clomipramine,Clozapine, Cocaine, Desipramine, Dexmethylphenidate, Diphenhydramine,Diphenhydramine, Disopyramide, Dobutamine, Dofetilide, Dolasetron,Domperidone, Dopamine, Doxepin, Dronedarone, Droperidol, Ephedrine,Epinephrine, Erythromycin, Escitalopram, Escitalopram, Famotidine,Felbamate, Fenfluramine, Flecamide, Fluconazole, Fluoxetine, Foscamet,Fosphenyloin, Galantamine, Gatifloxacin, Gemifloxacin, Granisetron,Halofantrine, Haloperidol, Ibutilide, Imipramine, Indapamide,Isoproterenol, Isoproterenol, Isradipine, Itraconazole, Ketoconazole,Lapatinib, Lapatinib, Levalbuterol, Levofloxacin, Levomethadyl,Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol, Methadone,Methylphenidate, Midodrine, Moexipril/HCTZ, Moxifloxacin, Nicardipine,Nilotinib, Norepinephrine, Nortriptyline, Octreotide, Ofloxacin,Ondansetron, Oxytocin, Paliperidone, Paroxetine, Pentamidine, Perflutrenlipid microspheres, Phentermine, Phenylephrine, Phenylpropanolamine,Pimozide, Probucol, Procainamide, Protriptyline, Pseudoephedrine,Quetiapine, Quinidine, Ranolazine, Risperidone, Ritodrine, Ritonavir,Roxithromycin, Salmeterol, Sertindole, Sertraline, Sibutramine,Solifenacin, Sotalol, Sparfloxacin, Sunitinib, Tacrolimus, Tamoxifen,Telithromycin, Terbutaline, Terfenadine, Thioridazine, Tizanidine,Tolterodine, Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib,Vardenafil, Venlafaxine, Voriconazole, Ziprasidone, and apharmaceutically acceptable salt thereof. 8.-9. (canceled)